Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
  • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
  • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/41—Preparation of salts of carboxylic acids
  • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the present invention relates to a process for the preparation of common intermediates which can be used for preparation of agents for urinary incontinence therapy, specifically to 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol and its prodrugs.
• Tolterodine (3-(2-hydroxy-5-methylphenyl)- N,N -diisopropyl-3-phenylpropylamine) is a muscarinic receptor antagonist for the treatment of overactive bladder including urinary incontinence. In the body it is converted to a hydroxy metabolite 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol (hydroxytolterodine, HT ), which is also an active molecule.
• HT 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol
• Hydroxytolterodine was firstly prepared in WO 94/011337 in a synthesis, which is extremely long. Similar approach was repeated in WO 99/058478 and optimised in WO 07/138440 , WO 07/144097 and WO 07/144091 . Described synthetic variations involve synthesis via bromo substituted lactone derivative (the bromo process) in 9 to 11 steps, in which some steps include reagents, unwanted in a routine industrial process such as Grignard reagents and aluminium hydrides.
• the bromo process is shown in three partial schemes.
• lactol is formed in one step by cinnamaldehyde.
• the lactol is then transformed further into HT by reaction with diisopropylamine and hydrogen gas in the presence of Pd/C.
• the formation of lactol suffers of low yield and by-products so it must be accomplished by use of amines and isolation of intermediate aminal ethers what makes process longer.
• Major issues with this synthesis are a use of heavy metals and of hydrogen gas. Synthesis is shown in Scheme 5.
• HT is prepared by oxidation of tolterodine.
• An oxidation of toluenic methyl group is not easy and demands protection of phenolic hydroxy group what essentially prolongs the synthesis of HT .
• the object of the present invention is to provide an industrially applicable, economical and acceptable process for obtaining key intermediates useful for synthesizing anticholinergic agents belonging to the class of 3,3-diphenylpropylamines, in particular for preparing hydroxytolterodine ( HT ), tolderodine or fesoterodine, respectively from readily available and optionally cheap and commercial starting compounds.
• HT hydroxytolterodine
• the invention relates to a synthesis of a compound of formula D or a salt thereof: wherein R 1 is selected from H, C 1 -C 6 alkyl, aryl substituted C 1 -C 2 alkyl, C 1 -C 4 -alkyl substituted silyl, Rx is selected from H and C 1 ⁇ C 3 alkyl; and Ry is selected from C 1 -C 3 alkyl, preferably Rx and Ry is isopropyl, comprising reacting a 3-phenylprop-2-en-1-amine of formula B or a salt thereof, wherein Rx and Ry are as defined above with hydroxyphenylglycine or a derivative thereof denoted by formula A in which * denotes chiral C atom, R 1 is selected from H, C 1 -C 6 alkyl, aryl substituted C 1 -C 2 alkyl, C 1 -C 4 -alkyl substituted silyl, R is hydrogen, C 1 -C 6 alkyl or aryl-
• the conversion of the formyl group in the obtained PHB is a very easy and efficient one for industrial purposes.
• the aldehyde PHB can then be converted to hydroxytolterodine ( HT ) in a reduction step, and can preferably further be converted to chiral ( R )- HT , further optionally converting HT or ( R )- HT to salts thereof.
• conversion to chiral ( R )- HT can be carried out with a process involving only one chemical step and one chiral separation step.
• an efficient synthesis of 3-(5-formyl-2-hydroxyphenyl)- N,N -diisopropyl-3-phenylpropylamine is provided to obtain a key intermediate for the synthesis of HT or salts thereof.
• HT can be used as an efficient inhibitor of muscarinic inhibitors, and preferably it can be further modified to obtain further useful therapeutic agents. For example it can be acylated to produce prodrugs for treatment of urinary incontinency.
• the invention relates to an embodiment wherein PHB , suitably via HT , is finally converted to fesoterodine or a salt thereof.
• Conversion can be carried out in only 3 steps using known protocols. These steps preferably include reduction using sodium borohydride, resolution of the product to ( R )-isomer via diastereomeric salt formation with ( R )-2-acetoxy(phenyl)acetic acid and subsequent esterification to fesoterodine.
• Fesoterodine can finally be converted into its salt, preferably into its fumarate salt by reaction with fumaric acid.
• 3-(3-(diisopropylamino)-l-phenylpropyl)-4-hydroxybenzaldehyde is synthesized comprising a reaction of 2-amino-2-(4-hydroxyphenyl)acetic acid (hydroxyphenylglycine) with N,N -diisopropyl-3-phenylprop-2-en-1-amine ( DIPCA ) in the presence of an acid, preferably at 80-150 °C, to give 2-amino-2-(3-(3-(diisopropylamino)-1-phenylpropyl)-4-hydroxyphenyl)acetic acid ( HFG ), and a further reaction with a suitable oxidant, preferably in water at 30-105 °C, to give PHB .
• Intermediate compound HFG can be isolated. But advantageously and preferably, the synthesis from DIPCA to PHB can be carried out in one pot, without intermediate isolation of HFG .
• Starting DIPCA can be prepared from cinnamyl chloride according to known procedure of WO 07/147547 or from other cinnamyl derivatives like cinnamaldehyde or cinnamyl alcohol by methods known to a skilled person. Analogously other N-substituted cinnamamines are prepared.
• Hydroxyphenylglycine is a cheap, commercially available starting material, known and used in production of semisynthetic beta-lactame antibiotics.
• DIPCA is reacted with 0.9 to 2, more preferably with 1 -1.4 molar equivalents of hydroxyphenylglycine compound of formula A as defined above, preferably in which C* has (R) or (S) configuration or a mixture thereof, R 1 is H, C 1 -C 6 alkyl, aryl substituted C 1 -C 2 alkyl, C 1 -C 4 -alkyl substituted silyl, R is hydrogen, C 1 -C 6 alkyl or aryl-C 1 -C 4 -akyl and Y is hydrogen or COR' in which R' is C 1 -C 4 alkyl, C 1 -C 4 alkoxy or benzyloxy, p-substituted benzyloxy, fluorenyloxy in a concentrated strong acid.
• R, R 1 and Y are H.
• the strong acid is selected from inorganic acids such as sulfuric and perchloric acid or organic sulfonic acids, such as C 1 -C 6 alkanesulfonic acids, fluorinated C 1 -C 6 alkanesulfonic acids, arenesulfonic acids, preferably the strong acid are selected from methanesulfonic and sulfuric acid.
• the strong acid is optionally diluted with water in preferably less than 50 % (w/w), most preferably less than 30 % (w/w) and / or with aliphatic acid, such as acetic acid.
• the reaction is carried out at 50-200°C, preferably at 80-150 °C, most preferably at 110-130 °C for 2 - 72 hours, preferably for 8 - 48 hours, most preferably for 20 - 24 hours.
• no organic solvent is contained in or added to the reaction solution for step (a), as this is beneficial for higher conversion rate and higher yield of reaction step (a).
• the intermediate product of Formula C can be isolated by dilution with water, adjusting of pH of water solution to 5-9, preferably to about 7 and optional extraction.
• the isolation can be accomplished by purification with column chromatography in order to characterise the obtained compound.
• the present invention in a further aspect relates to the provision of a compound of the formula C .
• R 1 is H, C 1 -C 6 alkyl, aryl substituted C 1 -C 2 alkyl, C 1 -C 4 -alkyl substituted silyl
• R is hydrogen, C 1 -C 6 alkyl or aryl-C 1 -C 4 -akyl
• Y is hydrogen or COR', in which R' is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, benzyloxy, p -substituted benzyloxy and fluorenyloxy
• Rx is selected from H and C 1 - C 3 alkyl
• Ry is selected from C 1 -C 3 alkyl (preferably R 1 is hydrogen, Rx and Ry is is isopropyl, Formula C ').
• HFG (formula C ', R, Y is H) as a most preferable molecule of the invention may be formed even from more general starting compounds of formula A ' (R and Y different from H) by spontaneous cleavage of labile R and Y groups during the condensation reaction in acidic conditions. If not, the preparation of HFG could be accomplished by an additional reaction of R and Y group cleavage, routine for a skilled person.
• the compound of formula C is thus useful in a process of preparing a medicament, especially for preparing an anticholinergic agent for treatment of urinary incontinence or overactive bladder.
• a preferred use of the compound HFG is for preparing hydroxytolterodine, tolterodine or fesoterodine, optionally as an enantiomeric pure form and further optionally in a salt form.
• isolation of the intermediate product HFG is not necessary and is dispensed with.
• HFG can be provided in a solution, optionally in a reaction solution or any worked-up solution, to be eventually used as useful intermediate for further purposes such as subsequent reaction steps.
• a water immiscible solvent selected from ethers or esters, preferably acetic esters is added and the intermediate is further submitted to reagents which convert it to aldehyde PHB .
• Transformation of amino acid compound HFG to aldehyde PHB is mechanistically three-step reaction.
• the amino group is oxidized to imino compound by treatment by an oxidant.
• the imino intermediate spontaneously hydrolyses in aqueous medium to ⁇ -keto acid which further decarboxylates at elevated temperature to the titled aldehyde.
• HFG is shown in reaction scheme 12 as an exemplified compound of formula C in which R 1 , Y and R respectively are H, and Rx and Ry are isopropyl, other compounds with different R 1 , Rx and Ry substituents as indicated can be analogously used.
• the oxidation/deamination step is carried out by transamination reagents selected from reactive aldehydes and ketones selected from sugars (preferably aldoses, such as glucose), quinones (such as benzoquinone), preferably transamination reagents are selected from ⁇ -keto substituted carbonyl compounds, more preferably from their C 2 -C 3 analogues, such as glyoxalic and pyruvic acids, salts, esters and aldehyde, most preferably from methylglyoxal.
• transamination reagents selected from reactive aldehydes and ketones selected from sugars (preferably aldoses, such as glucose), quinones (such as benzoquinone), preferably transamination reagents are selected from ⁇ -keto substituted carbonyl compounds, more preferably from their C 2 -C 3 analogues, such as glyoxalic and pyruvic acids, salts, esters and aldehyde, most preferably
• the oxidation is performed by air oxygen in the presence of catalytic amounts of radical catalysts, selected from organic compounds such as ascorbic acid or isatin or by transition metal cations, preferably selected from copper (II) salts.
• radical catalysts selected from organic compounds such as ascorbic acid or isatin or by transition metal cations, preferably selected from copper (II) salts.
• the introduction of oxygen is accomplished by vigorous stirring in atmospheric environment, optionally when larger volumes are used the introduction is done by blowing of air or oxygen directly into the reaction medium.
• the amino acid is oxidized by inorganic oxidants selected form salts which include metal cations in higher oxidation states (i.e. typically using a metal cation, (which naturally occurs in different lower and higher oxidation states), in its relatively high oxidation state), such as Fe 3+ or highly oxidized anions (i.e. typically using an anion, (which naturally occurs in different lower and higher oxidation states), in its relatively high oxidation states), such as nitrites and persulfates.
• inorganic persulfates preferably selected from alkali metal peroxodisulfates or, using peroxodisulfate species prepared in situ from corresponding sulfuric salts and hydrogen peroxide.
• potassium peroxodisulfate or sodium peroxodisulfate are used. Contrary to keto oxidants inorganic oxidants are not converted to organic by-products during oxidation process which is beneficial for purification process. Inorganic residues are simply washed by water and losses of product during purification are not higher than 10-15 % of yield in this case.
• Reaction of oxidative deamination/decarboxylation can be carried out at room temperature and above, preferably is carried out at 60°C and above, more preferably at reflux temperature (about 100°C such as up to 105°C), respectively for 0.5 to 24 hours, preferably 2-10 hours.
• the phases are separated and the product is isolated and purified by conventional methods. This can be illustrated by one but not limited example, in which the organic phase is extracted with hydrochloric acid solution, the water phase is alkalised to pH above 7 and the product is reextracted by a water immiscible solvent or mixture of solvents optionally followed by column chromatography purification. Therefore, the formyl intermediate PHB is prepared from cheap hydroxyphenylglycine derivatives and DIPCA in one-pot procedure not using Grignard and hydride reagents. Furthermore, no protection of phenolic group is needed for this conversion.
• PHB can then be further converted to hydroxytolterodine by reduction, preferably by using aluminumhydide or borohydride as reducing agent and more preferably with sodium borohydride in an alcohol such as methanol, and the product can be isolated by conventional methods, as can be depicted from scheme 11 (step from upper right to lower right side).
• HT as prepared by the process of the invention is typically and mostly racemic.
• chiral compound of formula A such as chiral ( R ) or (S) hydroxyphenylglycine, a slight enantiomeric excess could be achieved, typically of at most 20 %.
• separation of ( R ) enantiomer can be accomplished by crystallization with a chiral organic acid, preferably with ( R )-2-acetoxy(phenyl)acetic acid, wherein ( R )- HT is isolated from the precipitated diastereoisometric salt after alkalisation in highly enriched assay, as described in WO 07/138440 .
• enantiomers can be separated by chiral column chromatography or by any other enantiomer separation method known by a skilled person.
• ( R )- HT preferably its enantiomeric form ( R )- HT can be isolated in a solid state as a neutral molecule, or can be converted to a pharmaceutically acceptable salt.
• a preferred salt is mandelate.
• ( R )- HT can be converted to a prodrug molecule by acylation of phenolic hydroxy group by reactive derivatives of alkanoic acids, preferably it can be acylated by isobutyric chloride or anhydride to an isobutyrylated prodrug.
• fesoterodine is converted into a salt thereof, preferably fumarate salt.
• fesoterodine or a salt thereof (illustrated by its fumarate salt) can be depicted from scheme 13 below.
• This synthesis scheme starting from PHB or HT , involves only 3 or 2 steps, respectively to obtain fesoterodine.
• HT or salts of HT or fesoterodine can be used as an anticholinergic for treatment of diseases linked to muscarinic acceptor inhibition, such for the treatment of urinary incontinence or overactive bladder.
• tolterodine, HT or fesoterodine or any salts thereof is obtained as disclosed herein and subsequently formulated as an active pharmaceutical ingredient with a pharmaceutically acceptable carrier, known to those skilled in the art, to prepare a pharmaceutical composition for example in form of tablet, capsules, pellets, granules and suppositories or their combined forms.
• An amount of the anticholinergic agent notably of tolterodine, HT or fesoterodine or any salts thereof as the aforementioned active pharmaceutical ingredient, is suitable chosen to effect muscarinic acceptor inhibition and in particular to be effective for the treatment of urinary incontinence or overactive bladder.
• Pharmaceutical composition in accordance with present invention can be suitable for immediate release or modified release of tolterodine, HT or fesoterodine or any salts thereof obtained as disclosed herein.
• Solid pharmaceutical compositions can be for example coated with aim of increasing peletibility or regulating the disintegration or absorption.
• compositions may be selected from the group consisting of binders, diluents, disintegrating agents, stabilizing agents, preservatives, lubricants, fragrances, flavoring agents, sweeteners and other excipients known in the field of the pharmaceutical technology.
• carriers and excipients may be selected from the group consisting of lactose, microcrystalline cellulose, cellulose derivatives, (e.g. hydroxypropylcellulose, croscarmellose sodium), polyacrylates, calcium carbonate, starch, colloidal silicone dioxide, sodium starch glycolate, talc, magnesium stearate, mannitol, polyvinylpyrrolidone, polyethylene glycol and other excipients known in the field of the pharmaceutical technology.
• the title compound is prepared using the method described in WO 2007/147547 .
• a mixture of cinnamyl chloride (905 ml, 6.5 mol), diisopropylamine (1.37 1, 9.75 mol), potassium carbonate (0.90 kg, 6.5 mol), potassium iodide (54 g, 0.325 mol), toluene (2.1 l) and methanol (0.50 1) is stirred at reflux temperature for 20 hours.
• the mixture is cooled to 25 °C and water (5.2 1) is added. Phases are separated and the organic phase is extracted with brine.
• Organic phase is concentrated under reduced pressure (50 °C) and then water (10.4 1) and toluene (2.6 l) are added and the pH is adjusted to 2 by addition of concentrated hydrochloric acid (-500 ml).
• a mixture of DIPCA (1.09 g, 5 mmol), 4-hydroxybenzaldehyde (2.44 g, 20 mmol) and methanesulfonic acid (1.2 ml, 18 mol) is stirred at 100 °C for 3 hours. During this time the reaction mixture solidifies in a form of rubbery gel. The mixture is cooled to room temperature and left standing for 16 hours. HPLC analysis reveals 95 area % of 4-hydroxybenzaldehyde, 3 area % of DIPCA, and more than 15 minor products.
• the mixture is cooled to 25 °C and the phases are separated.
• Organic phase is extracted with 10 mM aqueous hydrochloric acid (100 ml).
• Aqueous phases are combined and pH is adjusted to 9 by addition 8 M aqueous sodium hydroxide.
• the title compound is prepared using the method described in WO 2007/147547 .
• a solution of PHB (6.33 g, 18.6 mmol) in methanol (40 ml) is cooled to 0 °C.
• sodium borohydride in portions and the solution is stirred for 2 hours.
• the solution is concentrated under reduced pressure and dichloromethane (50 ml) and 1 M aqueous hydrochloric acid are added (30 ml).
• the mixture is stirred for 5 min and the pH is adjusted to 8 using 1 M aqueous sodium hydroxide.
• the phases are separated and the aqueous phase is re-extracted four times with dichloromethane (4 x 30 ml).

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